PROINFLAMMATORY CYTOKINES REGULATE ANTIGEN-INDEPENDENT T-CELL ACTIVATION BY 2 SEPARATE CALCIUM-SIGNALING PATHWAYS IN MULTIPLE-SCLEROSIS PATIENTS

Central nervous system (CNS) lesions typical of multiple sclerosis (MS ) are characterized by demyelinating inflammatory infiltrates that con tain few CNS antigen-specific autoreactive T cells and a multitude of pathogenic non-antigen-specific mononuclear cells. Here, we report tha t in patients with MS the combined action of interferon-gamma (IFN gam ma), tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-2, and IL-6 leads to the activation of most peripheral T cells (mainly CD4 me mory) by promoting a persistent intracellular calcium increase via two independent signaling pathways. The activation of these pathways, one activated by IFN gamma and the other by the combination TNF alpha/IL- 2/IL-6, is independent from myelin antigens and precedes by 2 weeks ph ases of disease activity (eg, clinical relapses and/or appearance of g adolinium-enhancing lesions on brain magnetic resonance imaging scans during 1 year of follow-up). Our results indicate that an appropriate combination of the four cytokines, three with a proinflammatory profil e and one necessary for T-cell growth and differentiation, can activat e in an antigen-independent fashion most peripheral T cells from MS pa tients. This mechanism is likely to contribute to the recruitment of n onspecific lymphocytes into the cellular activation processes leading to CNS demyelination and may represent a major target for immune inter vention in MS.